While considerable progress has taken place in the past decade in our understanding of the molecular biology of human hemoglobin disorders, very little is known about the mechanism of the switch from fetal to adult hemoglobin synthesis. There is little doublt that if this switch could be manipulated in increase fetal hemoglobin (HbF) production, the clinical severity of such important disorders as sickle cell anemia (SCA) and thalassemia would be alleviated. Several studies have demonstrated considerable individual and population differences in the amount of HbF (Alpha2 Gamma2) present in the blood of patients with SCA. Furthermoe, the sickle cell trait phenotype is usually associated with normal HbF levles in all populations. These observations point to the role of genetic as well as homeostatic regulatory factors in the expression of the gamma globin genes. The purpose of the proposed research is to attempt to identify such factors. The approach to be followed relies on the observation of augmented HbF synthesis in peripheral blood erythroid progenitor cultures. The plan is to determine the rate of HbF production in patients with SCA after taking into account the selective survival of HbF contaning red cells. The proportion of HbF relative to HbA in erythroid colonies will be determined by high pressure liquid chromatography. Family studies will be carried out whereby a comparison will be made of the magnitude of augmentation of HbF synthesis in cultures from patients who are high Hb F producers and their families and those who are low producers and their families to uncover a hereditary component. In addition, either serum, conditioned media from peripheral blood cell subpopulations or urine extracts derived from high producers, will be added to cultures from low producers or normal controls to evaluate the contribution of homeostatic factors to the regulation of HbF synthesis. The coordinate synthesis of specific globin types and other red cell proteins will also be determined by two dimensional electrophoretic analysis.